With each era of discovery it seems there is always a leader with the innovative foresight and fortitude to lead a revolution and conquer a foe. The tools used to defeat the enemy are considered to be marvels and are viewed as such by outsiders willing to bask in their glory and enjoy the fruits of their successes. Meanwhile, there are always those desiring to dissect the technology, glean from it whatever knowledge is obtainable and reverse engineer it to develop their own wares from it to benefit them and their potential customer base with their own "new" product.
Dendreon received the FDA's approval to market Provenge in April of 2010 for asymptomatic or minimally symptomatic hormone-refractory prostate cancer. Provenge is a revolutionary, first-in-class immunotherapy treatment that is designed to cause an immune response against prostatic acid phosphatase (PAP), an antigen that is expressed in most prostate cancers. Provenge's approval legitimized an entirely new approach to fighting cancer. Previous standards of care included resection, chemotherapy, hormone therapy and/or radiotherapy. Although each had its merits, each also had its drawbacks ranging from disfigurement, toxicities, immune system compromise and a host of secondary illnesses often due to the patients' immune system compromise. Provenge's approach works with the patients' immunity systems rather than compromising it. In a sense, it teaches the immunity system that the PAP antigen is foreign and it should be attacked as such. The on-going battle against cancer is partly made more difficult by the fact that the body doesn't recognize the cancer cells as foreign and either ignores them, or even nourishes them, as evident by the mass of blood vessels supplying the solid tumors of some cancers.
Provenge was revolutionary in the respect that it ushered in a whole new era of cancer treatment. Since its approval, other companies have attempted to put their spin on the technology with clinicals underway to treat a host of other cancers. Galena Biopharma (GALE) has been one of the most successful of these with its NeuVax therapy to treat breast cancer. While applying the same immunotherapy concept to work using the patient's own immunity system to fight the disease, NeuVax is indeed a next generation treatment relative to Provenge. No degree of disrespect is meant for what Provenge has done to the field of cancer treatment and for the hope it gives the intended prostate cancer patient set. It was and still is a marvel and a revolutionary treatment regimen, and Dendreon will likely continue to make millions on it. Additional research and perfecting of Dendreon's methodology was inevitable as with any technology and Galena looks to be taking full advantage of the immunotherapy evolution.
The NeuVax vaccine consists of the E75 peptide derived from the HER2 protein which is found on about 75% of breast cancers and a host of other cancers. The vaccine is combined with the immune adjuvant granulocyte macrophage colony stimulating factor (GM-CSF). When injected intradermally, NeuVax stimulates cytotoxic CD8+ T cells in a highly specific manner to target cells expressing HER2. The Phase III PRESENT trial for NeuVax initiated enrollment earlier this year and is focusing on breast cancer patients with low to moderate (HER2 +1 and +2) levels of the HER2 expression. This part of the HER2 breast cancer patient set comprises about 50% of breast cancers and represents an unmet need as the highly expressed (HER2 +3) set is currently treated with the $5 billion per year revenue-generating Herceptin produced by Roche-Genentech (RHHBY).
While NeuVax and Provenge each are both immunotherapy drugs with staunch investor followings, the two are very different in terms of mechanisms, preparation, targeted patient set, parent companies and other characteristics. Prostate and breast cancers each have huge unmet needs in society. Each has several degrees of progression, sub-types and prognoses beyond the scope of the article. To give an over-simplified comparison, the Center for Disease Control's website for cancer statistics can be consulted. Although not a breakdown of the many sub-types of each cancer, it does convey the prevalence of the diseases and their need for a cure. Their latest reported composite data from SEER, NPCR and NCI from 2007 reported an age-adjusted 156.9 newly-reported cases of prostate cancer and 120.4 newly-reported cases of breast cancers per 100,000 people. To put the unmet need in perspective, however, the number of deaths is more relevant. The same website reports an ominous 23.5 age-adjusted deaths for overall prostate cancer and 22.8 age-adjusted deaths for breast cancer (breast cancer data is for women only) per 100,000 patients, both unacceptable numbers for a developed country with about 310 million citizens. Provenge's approval is only for the metastatic, castrate-resistant prostate, but these numbers weren't specifically available. NeuVax's initial indication is expected to target HER2 +1 and +2 expressions or 50% of breast cancer cases.
NeuVax and Provenge differ radically in their manufacturing and administrations. Provenge is an autologous vaccine. It is derived from and manufactured from cells extracted from the patient to be treated. The process is slow, labor- intensive, involves many steps (many steps could mean more areas for potential manufacturing problems and contamination) and lastly, expensive. Steps of its production require blood withdrawal and subsequent leukapheresis, a process in which the white blood cells (containing antigen-presenting cells) are separated from the sample. These cells are then packaged and shipped to one of Dendreon's manufacturing facilities. These cells are then co-cultured with prostatic acid phosphatase (PAP)-containing recombinant fusion protein. PAP is used because it is over-expressed on 95% of prostate cancers, a solid antigen target. The end product of the process is PAP linked to GM-CSF, a vaccine that teaches T cells and other immune system components to target and destroy the PAP expression cells. The manufacturing process takes two days, and the patient can receive his first treatment approximately 3 days after his blood was collected. The treatment regimen consists of 3 dosages infused over the period of 4 weeks.
NeuVax is an off-the-shelf or allogeneic drug and not made "as needed". The therapy is readily available and ready for immediate administration upon diagnosis and subsequent standard of care treatment of resection, radiotherapy or chemotherapy (or some combination thereof). After this first-line treatment, NeuVax is administered once per month for six months as part of its initial regimen. Patients would then receive additional doses once every six months as boosters to keep the patients' immune system responses strong. The off-the-shelf preparation is key for NeuVax as it contributes to keeping the cost of the drug low relative to Provenge's $31K per infusion or $93K for the three-treatment regimen. Preliminary costs for NeuVax meanwhile are $1000 per dose. Dendreon did have sluggish initial sales partly due to the cost of the drug and reimbursement issues with the administering physicians paying for the therapy up front and having to await payment from insurance. At first, Medicare even balked at the treatment cost. However, many of those issues have now been resolved and the revenue stream has begun to increase.
Provenge's 2010 approval was based on a 512 patient set double-blind placebo-controlled Phase III trial in which median overall survival increased 4.1 months to 25.8 months versus 21.7 months for patients receiving the placebo, an apparently marginal efficacy depending on vantage point. Subsequent data analysis of the trial data has given a more positive spin on the data, but nothing official about these analyses has been released from Dendreon. Upcoming ASCO presentations and real-world data acquisition of the patients treated since the drug has been marketed should shine some light on the efficacy in the coming months. NeuVax's Phase III trial initiated in January, so no data is yet available for it (likely Q1 2013). The Phase II data, for which the trial design is based on, had a 53 patient subset receiving at least one booster inoculation (once every six months) with impressive efficacy as evident in a statistically significant disease-free survival rate of 95.9% versus 79.7% in the control group (p = 0.016). To keep things in perspective, Provenge is used as a first-line treatment with a much more difficult job to accomplish in attacking the tumor itself. NeuVax, has a theoretically easier job of attacking residual or newly-formed HER2 +1/+2 expressed cells/tumors in an adjuvant setting after the initial standard of care treatment to shrink and remove the cancer initially. NeuVax is intended to prevent recurrence while Provenge fights on the front lines.
Lastly is the all-important aspect of safety, as efficacy with a less-than-acceptable safety profile means little. Provenge's autologous preparation should be a safety benefit as the treatment is manufactured from the patients' own cells. This should greatly reduce any immune system rejection of the therapy. The FDA approval announcement did mention some issues with the safety profile despite the therapy's acceptance. Virtually all patients receiving Provenge had an adverse reaction of some kind. The majority of the reactions were mild or moderate in severity and included chills, fatigue, fever, back pain, nausea, joint ache and headache. Serious adverse events were reported in on quarter of the patients with some acute infusion reactions and stroke. Cerebrovascular events, including hemorrhagic and ischemic strokes, were noted in 3.5 percent of patients compared to 2.6 percent of patients in the control group. Conversely, the NeuVax Phase II patient set with all patients passing the 3 year landmark has had an extremely promising safety profile with no serious adverse events reported. The most commonly reported treatment-related issues in the combined node-positive and node-negative trials were redness, induration at the injection site, erythema, pruritis, or discomfort requiring medication. The most common systemic toxicities were bone pain, flu-like symptoms, fatigue, headache, and myalgias (attributed to GM-CSF and short in duration). Most toxicities in the two studies combined were mild (Grade 1 or 2). Three Grade 3 events of bone pain, back pain, and angioedema, and no Grade 4 or 5 AEs were reported. A NeuVax/Provenge comparison for safety shows a clear advantage to NeuVax at this point. However, when comparing either to the side effects associated with the typical chemotherapy regimen, the winner in either case is the targeted patient set.
Dendreon has solidified its position in the pharmaceutical sector with its revolutionary and first-in-class method of attacking cancer through an immunotherapy approach. It has now gone beyond development Phase and is now marketing its product and generating revenue to the tune of $82 million in Q1 2012 compared to $27 million for the same quarter in 2011, a sure sign of the drug's increasing popularity and stream-lined cost reimbursement program. The therapy is still expensive to manufacture and does affect the company's bottom line with a net loss of $103.9 million for Q1. Hopefully the company can streamline its manufacturing process and reduce the costs over the coming years making it more advantageous for the company and its patients. With a $1.40 billion dollar market capitalization and $559.1 million in cash, cash equivalents, as well as short-term and long-term investments, the company does need to continue to improve in that regard as it marches toward profitability.
Galena Biopharma is still in development stage with Phase III interim data in about a year that will be highly indicative of what could be in store for the final Phase III results and the company's future. With a $75 million market capitalization, the upside for investors could be substantial with a huge potential patient set as evident by Herceptin's $5 billion in sales for its portion of the HER2 patient set. The Phase II trial performed as it intended with safety and efficacy determined, especially for the booster dose portion of the trial. As the anticipation of the interim Phase III results will begin to grow in the coming months, more investors will likely begin hedging their bets on the upcoming data. Almost as revealing, however, will be the 48-month follow up to the Phase I/II NeuVax trial at ASCO. Confirmation of the booster-set portion of the trial will further confirm the trial design of the Phase III now underway and will give investors even more reason to take heed along with potential Big Pharma suitors.
Dendreon's stock still has some potential upside if ongoing trial data impresses, along with data collected from patients treated since the 2010 approval. The greater upside between the two will likely be with Galena as ASCO updates are fast approaching in early June, the Phase II trial initiates in partnership with Genentech/Roche where NeuVax will be used in conjunction with Herceptin (and the obvious rumors starting to emerge about the Galena/Roche relationship), and the likely run up by the end of 2012 with the PRESENT interim data approaching. The mere anticipation of these catalysts should be chart movers while positive data will accentuate the upside even more so. The immunotherapy approach to fighting cancer has been validated thanks to Provenge. Galena Biopharma and cancer sufferers owe a great deal of thanks and respect to Dendreon for paving the way. Now, the next generation of the immunotherapy approach is emerging hopefully with better safety profiles and efficacy. There will be many variations on the theme of immunotherapy treatment of cancer with many failures and few successes likely. Time will only tell in which group Galena Biopharma will be part of. If ongoing and upcoming data confirm the 52 patient subset and its apparent success with the NeuVax boosters keeping the efficacy strong, breast cancer sufferers and company shareholders have a great deal of hope coming. 2012 and 2013 will be very telling times in the history of each of these modern immunotherapy wonders.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.
